Hypothalamic obesity (HO) occurs in patients with tumors and lesions in the medial hypothalamic region. Hypothalamic dysfunction can lead to hyperinsulinemia and leptin resistance. This study is focused on HO caused by craniopharyngiomas (CP), which are the most common childhood brain tumors of nonglial origin. Despite excellent overall survival rates, CP patients have substantially reduced quality of life because of significant long-term sequelae, notably severe obesity in about 50% of patients, leading to a high rate of cardiovascular mortality. Recent studies reported that both hyperphagia and decreased energy expenditure can contribute to severe obesity in HO patients. Previous drug intervention studies were either too small or showed only moderate effects, and it is not clear which biological factors are responsible for successful intervention. Some anti-obesity drugs that require intact hypothalamic signaling pathways for appetite inhibition show poor efficacy in patients with HO. Based on promising results using a glucagon-like-peptide-1 receptor agonist (GLP1RA) in obese adolescents with and without HO, as well as in rodents with HO, the proposed multicenter study will test the effect of the GLP1RA exenatide once weekly extended-release (ExQW) on clinical outcomes and metabolic function in a 36 week double-blind, placebo-controlled randomized trial followed by a 18 week open label extension. Forty-eight subjects will be randomized to GLP1RA (24) or placebo (24). The overall hypothesis is that in severely obese HO subjects with extended hypothalamic damage, drugs causing weight loss via hindbrain signaling, such as GLP1RAs, will reduce body weight, providing a desperately needed non-surgical option for treatment of HO. We recognize that there may be variability of treatment response and will therefore also test potential behavioral, metabolic, and neuroradiological predictors of treatment response. The primary endpoint is to test long-term efficacy of GLP1RA treatment on body mass index reduction after 36 weeks. Secondary endpoints include changes in body composition, parameters of metabolic syndrome, free-living total energy expenditure, appetitive behavior, physical activity, hormonal parameters of energy homeostasis and insulin resistance. Specific Aim (SA) 1 will test if GLP1RA treatment will lead to reduced BMI. SA 2 will test if GLP1RA improves adiposity, cardiometabolic risk factors, glucose tolerance and hyperinsulinemia. SA 3 will include exploratory studies in order to test if GLP1RA will lead to changes in energy intake and expenditure. SA 3 will also test innovative predictors of GLP1RA treatment outcomes such as pretreatment hyperphagia, energy expenditure, serum leptin and the severity of the hypothalamic lesion assessed by a novel neuroimaging score obtained prior to study intervention. The study is guided by an integrated transdisciplinary team. The goals are to implement cost-effective treatments to improve HO outcomes, and to get fundamental mechanistic insights into GLP-1 physiology and factors that determine treatment success, which are also relevant for other forms of obesity.